Tadalafil

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 50090-6945

Application: ANDA209908

Effective: 20231226

1 INDICATIONS & USAGE Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: • erectile dysfunction (ED) ( 1.1 ) • the signs and symptoms of benign prostatic hyperplasia (BPH) ( 1.2 ) • ED and the signs and symptoms of BPH (ED/BPH) ( 1.3 ) If tadalafil tablet is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks ( 1.4 ). 1.1 Erectile Dysfunction Tadalafil tablet is indicated for the treatment of erectile dysfunction (ED). 1.2 Benign Prostatic Hyperplasia Tadalafil tablet is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). 1.3 Erectile Dysfunction and Benign Prostatic Hyperplasia Tadalafil tablet is indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH). 1.4 Limitation of Use If tadalafil tablet is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of tadalafil tablets decreases from 4 weeks until 26 weeks, and the incremental benefit of tadalafil tablets beyond 26 weeks is unknown [see Clinical Studies ( 14.3 )].

2 DOSAGE & ADMINISTRATION • Tadalafil tablet for use as needed: • ED: Starting dose: 10 mg as needed prior to sexual activity. Increase to 20 mg or decrease to 5 mg based upon efficacy/tolerability. Improves erectile function compared to placebo up to 36 hours post dose. Not to be taken more than once per day (2.1). • Tadalafil tablet for once daily use: • ED: 2.5 mg taken once daily, without regard to timing of sexual activity. May increase to 5 mg based upon efficacy and tolerability ( 2.2 ). • BPH: 5 mg, taken at approximately the same time every day ( 2.3 ) • ED and BPH: 5 mg, taken at approximately the same time every day ( 2.3 , 2.4 ) • Tadalafil tablets may be taken without regard to food ( 2.5 ). 2.1 Tadalafil Tablets for Use as Needed for Erectile Dysfunction Do not split tadalafil tablets; entire dose should be taken. • The recommended starting dose of tadalafil tablets for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity. • The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients. • Tadalafil tablets for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of tadalafil tablets, this should be taken into consideration. 2.2 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction • The recommended starting dose of tadalafil tablets for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. • The tadalafil tablets dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability. 2.3 Tadalafil Tablets for Once Daily Use for Benign Prostatic Hyperplasia • The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day. • When therapy for BPH is initiated with tadalafil tablets and finasteride, the recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks. 2.4 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction and Benign The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. 2.5 Use with Food Tadalafil tablets may be taken without regard to food. 2.6 Use in Specific Populations Renal Impairment Tadalafil Tablets for Use as Needed • Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours. • Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.7 )]. Tadalafil Tablets for Once Daily Use Erectile Dysfunction • Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended [ see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.7 )]. Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia • Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended. An increase to 5 mg may be considered based on individual response. • Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.7 )]. Hepatic Impairment Tadalafil Tablets for Use as Needed • Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of tadalafil tablets once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised. • Severe (Child Pugh Class C): The use of tadalafil tablets is not recommended [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.6 )]. Tadalafil Tablets for Once Daily Use • Mild or moderate (Child Pugh Class A or B): Tadalafil tablets for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to these patients. • Severe (Child Pugh Class C): The use of tadalafil tablets is not recommended [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.6 )]. 2.7 Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated [see Contraindications ( 4.1 )]. Alpha-Blockers ED — When tadalafil tablet is coadministered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and tadalafil tablets should be initiated at the lowest recommended dose [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )]. BPH — Tadalafil tablet is not recommended for use in combination with alpha-blockers for the treatment of BPH [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )]. CYP3A4 Inhibitors Tadalafil Tablets for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of tadalafil tablets is 10 mg, not to exceed once every 72 hours [see Warnings and Precautions ( 5.10 ) and Drug Interactions ( 7.2 )]. Tadalafil Tablets for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg [see Warnings and Precautions ( 5.10 ) and Drug Interactions ( 7.2 )].

4 CONTRAINDICATIONS • Administration of tadalafil tablets to patients using any form of organic nitrate is contraindicated. Tadalafil tablets was shown to potentiate the hypotensive effect of nitrates ( 4.1 ). • History of known serious hypersensitivity reaction to tadalafil tablets or ADCIRCA ® ( 4.2 ). • Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4.3 ). 4.1 Nitrates Administration of tadalafil tablets to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil tablets was shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology ( 12.2 )]. 4.2 Hypersensitivity Reactions Tadalafil tablet is contraindicated in patients with a known serious hypersensitivity to tadalafil (tadalafil tablets or ADCIRCA ® ). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions ( 6.2 )]. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use tadalafil tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including tadalafil tablets, may potentiate the hypotensive effects of GC stimulators.

Not available.

6 ADVERSE REACTIONS Most common adverse reactions (≥2%) include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and pain in limb ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tadalafil was administered to over 9,000 men during clinical trials worldwide. In trials of tadalafil for once daily use, a total of 1,434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For tadalafil for use as needed, over 1,300 and 1,000 subjects were treated for at least 6 months and 1 year, respectively. Tadalafil for Use as Needed for ED In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients. When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported ( see Table 1) for tadalafil for use as needed: Table 1: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Tadalafil (10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled Clinical Studies (Including a Study in Patients with Diabetes) for Tadalafil for Use as Needed for ED a The term flushing includes: facial flushing and flushing Adverse Reaction Placebo (N=476) Tadalafil 5 mg (N=151) Tadalafil 10 mg (N=394) Tadalafil 20 mg (N=635) Headache 5% 11% 11% 15% Dyspepsia 1% 4% 8% 10% Back pain 3% 3% 5% 6% Myalgia 1% 1% 4% 3% Nasal congestion 1% 2% 3% 3% Flushing a 1% 2% 3% 3% P ain in limb 1% 1% 3% 3% Tadalafil for Once Daily Use for ED In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8% in placebo-treated patients. Table 2: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Tadalafil for Once Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes) for Tadalafil for Once Daily Use for ED Adverse Reaction Placebo (N=248) Tadalafil 2.5 mg (N=196) Tadalafil 5 mg (N=304) Headache 5% 3% 6% Dyspepsia 2% 4% 5% Nasopharyngitis 4% 4% 3% Back pain 1% 3% 3% Upper respiratory tract infection 1% 3% 3% Flushing 1% 1% 3% Myalgia 1% 2% 2% Cough 0% 4% 2% Diarrhea 0% 1% 2% Nasal congestion 0% 2% 2% Pain in extremity 0% 1% 2% Urinary tract infection 0% 2% 0% Gastroesophageal reflux disease 0% 2% 1% Abdominal pain 0% 2% 1% The following adverse reactions were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study: Table 3: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Tadalafil for Once Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Tadalafil for Once Daily Use for ED Adverse Reaction Placebo (N=94) Tadalafil 2.5 mg (N=96) Tadalafil 5 mg (N=97) Nasopharyngitis 5% 6% 6% Gastroenteritis 2% 3% 5% Back pain 3% 5% 2% Upper respiratory tract infection 0% 3% 4% Dyspepsia 1% 4% 1% Gastroesophageal reflux disease 0% 3% 2% Myalgia 2% 4% 1% Hypertension 0% 1% 3% Nasal congestion 0% 0% 4% Tadalafil for Once Daily Use for BPH and for ED and BPH In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported ( see Table 4). Table 4: Treatment-Emergent Adverse Reactions Reported by ≥1% of Patients Treated with Tadalafil for Once Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo-Controlled Clinical Studies of 12 Weeks Treatment Duration, including Two Studies for Tadalafil for Once Daily Use for BPH and One Study for ED and BPH Adverse Reaction Placebo (N=576) Tadalafil 5 mg (N=581) Headache 2.3% 4.1% Dyspepsia 0.2% 2.4% Back pain 1.4% 2.4% Nasopharyngitis 1.6% 2.1% Diarrhea 1% 1.4% Pain in extremity 0% 1.4% Myalgia 0.3% 1.2% Dizziness 0.5% 1% Additional, less frequent adverse reactions (<1%) reported in the controlled clinical trials of tadalafil for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm. Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency (<5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with tadalafil for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for tadalafil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of tadalafil for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of <1% across all indications. Across placebo-controlled studies with tadalafil for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil (2.5% of patients) [see Use in Specific Populations ( 8.5 )]. Across all studies with any tadalafil dose, reports of changes in color vision were rare (<0.1% of patients). The following section identifies additional, less frequent events (<2%) reported in controlled clinical trials of tadalafil for once daily use or use as needed. A causal relationship of these events to tadalafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful: Body as a Whole — asthenia, face edema, fatigue, pain, peripheral edema Cardiovascular — angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia Digestive — abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage Musculoskeletal — arthralgia, neck pain Nervous — dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo Renal and Urinary — renal impairment Respiratory — dyspnea, epistaxis, pharyngitis Skin and Appendages — pruritus, rash, sweating Ophthalmologic — blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase, swelling of eyelids Otologic — sudden decrease or loss of hearing, tinnitus Urogenital — erection increased, spontaneous penile erection 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tadalafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Cardiovascular and Cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions ( 5.1 )]. Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis Nervous — migraine, seizure and seizure recurrence, transient global amnesia Ophthalmologic — visual field defect, retinal vein occlusion, retinal artery occlusion Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking [see Warnings and Precautions ( 5.4 )]. Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions ( 5.5 )]. Urogenital — priapism [see Warnings and Precautions ( 5.3 )].